There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease), which form inactive complexes with the MP's.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 1970, 52A, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteases. The available evidence supports that it is the metalloproteases that are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 1978, 21, 761-766, Woessner et al. Arthritis Rheum. 1983, 26, 63-68 and Woessner et al. Arthritis Rheum. 1984, 27, 305-312). In addition, aggrecanase has been identified as providing the specific cleavage product of proteoglycan found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 1993, 36, 1214-22).
Therefore, metalloproteases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 1990, 25, 175-184, AP, San Diego).
Tumor necrosis factor-α (TNFα) is a cell-associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNFα has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNFα has been shown to be lethal. There is now considerable evidence that blocking the effects of TNFα with specific antibodie's can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al. Lancet 1994, 344, 1105), non-insulin dependent diabetes melitus (Lohmander, L. S. et al. Arthritis Rheum. 1993, 36, 1214-22) and Crohn's disease (MacDonald et al. Clin. Exp. Immunol. 1990, 81, 301).
Compounds which inhibit the production of TNFα are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently, TNFα converting enzyme (TACE), the enzyme responsible for TNFα release from cells, were purified and sequenced (Black et al. Nature 1997, 385, 729; Moss et al. Nature 1997, 385, 733). This invention describes molecules that inhibit this enzyme and hence the secretion of active TNFα from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, malaria, Crohn's disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF-α production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF-α production may also have a particular advantage in diseases where both mechanisms are involved.
Prostaglandins (PG) play a major role in the inflammation process and the inhibition of PG production has been a common target of anti-inflammatory drug discovery. Many NSAIDS have been found to prevent the production of PG by inhibiting the enzyme cyclooxygenase (COX). Among the two isoforms of COXs, COX-1 is constitutively expressed. COX-2 is an inducible isozyme associated with inflammation. Selective COX-2 inhibitor was believed to maintain the efficacy of traditional NSAIDs, which inhibit both isozymes, and produce fewer and less drastic side effects. As a result, development of selective COX-2 inhibitors has attracted major interest in the pharmaceutical industry. Because of the significant roles of PGs and TNF-α in inflammation, combined use of COX-2 and TACE inhibitors may have superior efficacy to either therapy alone in some inflammatory diseases.
U.S. Pat. No. 6,048,877 discloses antiarrhythmic agents of the following formula: wherein R3 can be a spiro-hydantoin moiety; R5 is (4-phenyl-1-piperidinyl)ethyl; n is 0-2; and R1, R2, and R4 are a variety of groups. Compounds specifically described in U.S. Pat. No. 6,048,877 are not considered to be part of the present invention.
WO01/44217 and WO99/24416 describe cyclin dependent kinases inhibitors of the following formula: wherein R3 is aryl or heteroaryl; R1 and R2 are independently H, F or alkyl; n is 1-3; m is 0-2; and R4 can be —CO-alkylene-hydantoin or —CONH-alkylene-hydantoin. Compounds specifically described in WO01/44217 and WO99/24416 are not considered to be part of the present invention.
WO01/23363 describes matrix metalloproteinase 13 and aggrecanase inhibitors of the following formula: wherein R1 is OH or optionally protected hydroxamino; R2 can be a hydantoin moiety; R4 can be aryl or heteroaryl; L is arylene or heteroarylene; and M is O or S. Compounds specifically described in WO01/23363 are not considered to be part of the present invention.
WO01/12189 discloses antitumor agents of the following formula: wherein R is a C3-C6 cycloalkyl; and R1 can be —CH2-hydantoin. Compounds specifically described in WO01/12189 are not considered to be part of the present invention.
WO00/35886 illustrates serine protease inhibitors of the following formula: wherein R2 can be —OCH2CH2NHCOCH2-hydantoin; and R1, R3-R8, and R20 are a variety of groups. Compounds specifically described in WO00/35886 are not considered to be part of the present invention.
U.S. Pat. No. 5,861,380 depicts serine protease inhibitors of the following formula: wherein R1 can be aryl, aralkyl, heteroaryl or heteroaralkyl; X and Y are N, O or S; R11, R12 and E can form a hydantoinyl moiety; R2, R3, R′2, and R′3 are a variety of groups. Compounds specifically described in U.S. Pat. No. 5,861,380 are not considered to be part of the present invention.
U.S. Pat. No. 5,811,459 describes analgesics & prostaglandin antagonists of the following formula: wherein R can be —CH2-hydantoin. Compounds specifically described in U.S. Pat. No. 5,811,459 are not considered to be part of the present invention.
U.S. Pat. No. 5,567,725 discloses glucose-6-phosphatase inhibitors of the following formula: wherein R1 can be a hydantoin moiety; X can be —CH2—O—CH2—, —CH2—S—CH2—, or —CH2—NR8—CH2—; Y is (CH2)0-4, O, S or NR8; Z is a linear linker, C3-C10-cycloalkylene, or C3-C10-cycloalkenylene; R3 can be cycloalkyl, aryl or heteroaryl; and R4, R5, and R6 are a variety of groups. Compounds specifically described in U.S. Pat. No. 5,567,725 are not considered to be part of the present invention.
U.S. Pat. No. 5,821,241 illustrates fibrinogen receptor antagonists of the following formula: wherein Q can be a 4-9 membered mono or bicyclic heterocyclic ring system; n is 0-7; a is an amide linker or a bond; AB is a fused ring system sharing adjacent C and N atoms in which each ring is a 5-7 membered saturated or unsatuarated ring containing 1-3 heteroatoms selected from O, S or N; R5 can a bond, CH, —CH(CH2)n, or —C(O)(CH2)n; R1 and R6 can form a hydantoinyl moiety; and R6 are a variety of groups. Compounds specifically described in U.S. Pat. No. 5,821,241 are not considered to be part of the present invention.
U.S. Pat. No. 4,816,454 discloses compounds of the following formula: wherein R10 can be —CH2-hydantoin; and R4, R5, and R6 are a variety of groups. Compounds specifically described in U.S. Pat. No. 4,816,454 are not considered to be part of the present invention.
The compounds of the present invention act as inhibitors of MPs, in particular TACE, MMPs, and/or aggrecanase. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibition of aggrecanase, TACE, and other metalloproteases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA.